PROJECT SUMMARY/ABSTRACT Objectives: The goal of this project is to identify molecular markers of preclinical pulmonary fibrosis in order to develop a predictive model to detect early idiopathic pulmonary fibrosis (IPF). Relationship to health: IPF is characterized by progressive scarring of the lung parenchyma, has a median survival of 3 years from time of diagnosis, affects 5 million patients worldwide, and is increasing in prevalence. There are few approved therapies for IPF and no curative medical therapies. Relatives of Familial Interstitial Pneumonia (FIP) patients are at higher risk than the general population of developing IPF. Most patients with IPF are diagnosed when the disease is advanced?earlier diagnosis of IPF would detect patients with more intact lung tissue and reveal targets for early intervention, potentially shifting the IPF treatment paradigm from palliation to prevention. Rationale: Preliminary data show that 16% of FIP relatives have evidence of preclinical pulmonary fibrosis. Analysis of peripheral blood gene expression illustrates that those with preclinical pulmonary fibrosis have a distinct gene expression profile. Hypothesis: Peripheral blood molecular signatures can be utilized to identify preclinical pulmonary fibrosis in at-risk individuals and early findings of pulmonary fibrosis in this at-risk cohort are a precursor to progressive disease. Specific Aim 1: Discover and validate epigenetic marks and proteins in peripheral blood associated with early fibrosis and determine the relationship of significant epigenetic marks to differential gene expression. Focusing on differentially methylated regions and plasma proteins previously associated with IPF, peripheral blood DNA methylation and plasma protein levels will be measured to identify regions associated with early pulmonary fibrosis. Existing gene expression data will be used to characterize the relationship between DNA methylation and gene expression. Specific Aim 2: Utilizing significant molecular markers from gene expression data and those discovered in Aim 1, a predictive model to identify early pulmonary fibrosis in this at-risk cohort will be developed. Specific Aim 3: Determine the prevalence, progression, and radiographic characteristics of pulmonary fibrosis in FIP relatives and test our predictive model in those with de novo pulmonary fibrosis during the study period. Five years after their initial thoracic CT scan, FIP relatives will undergo repeat thoracic imaging and blood draw. We will determine (1) the number of subjects developing de novo fibrosis since initial scan and (2) radiographic features of progressive fibrosis. Secondarily, we will examine the validity of our predictive model from Aim 2 to identify those who develop de novo fibrosis. Career Development: The candidate has a long- term commitment to academic medicine and translational research in pulmonary fibrosis. She is a member of a supportive research group and institution with a long history of studying IPF. The hands-on experience, comprehensive mentorship, cross-institutional collaboration, and didactic training proposed will prepare the principal investigator for an independent career in translational research in the field of advanced lung diseases.